Propargyl benzamides



United States Patent 3,481,079 PROPARGYL BENZAMIDES Bruce Wayne Horrom, Waukegan, and Aldo Joseph Crovetti, Lake Forest, Ill., assignors to Abbott Laboratories, North Chicago, 11]., a coproration of Illinois No Drawing. Filed Mar. 6, 1967, Ser. No. 620,651

Int. Cl. C07c 103/22, 103/34; A61k 27/00 US. Cl. 260-558 23 Claims ABSTRACT OF THE DISCLOSURE Substituted propargyl benzamides having the formula 0 X RgNH-( 3CECH useful as biocidal agents.

This invention is directed to a novel series of chemical compounds, and more particularly, to a series of substituted propargyl benzamides having the formula wherein X and Y each signify hydrogen and loweralkyl having 1 to 4 carbon atoms, and R represents a substituted phenyl radical. These compounds are useful as anti-bacterial, anti-protozoal and anti-fungal agents.

The activity of these compounds is believed to be dependent upon the presence of the 2-propynyl moiety as well as the particular substituted phenyl radical. The substituted phenyl radicals considered to be within the scope of this invention include:

2-chlorophenyl, 3-chlorophenyl, 4-ch1orophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 2,4-dichlorophenyl, 2,5- dichlorophenyl, 2 chloro 4 nitrophenyl, 3,5-dinitro-4- chlorophenyl, 2 methyl 3,5 dinitrophenyl, 2 nitro5- chlorophenyl, 2 chloro 3,5 dinitrophenyl, 3,5 dinitro- 4 alkylaminophenyl, 3,5 dinitro 4 dialky1aminophenyl, 2,4 dichloro 3,5 dinitrophenyl, 3 nitro 4- chlorophenyl, 2 hydroxy 3,5 dibromophenyl, 3,5- dihalo 4 hydroxyphenyl, 2,4,6 triiodo 3 hydroxyphenyl, 2 hydroxy 3,5 diiodophenyl, 2 hydroxy 5- halophenyl, 3,5-dichloro-4-halophenyl.

' These new compounds are useful as anti-bacterial, antifungal and anti-protozoal agents, and can be employed as the active components of disinfectant compositions. These compounds effectively control a variety of microorganisms such as Chaetomium globosum, Myrothesium verrucaria, Alternaria, Rhizopus nigricans, Staphlococcus aureus, T richomonas vaginalis, Asperigillus versicolor, Penicillium citrinum and Fusarium oxysporum. In such use, the compounds are dispersed in an inert solid, or dispersed or dissolved in a suitable solvent and applied as a dust or spray. In a typical application, the compound 2,6 dichloro N (1,1 dimethylpropargyl) benzamide completely inhibit the growth of Chaetomium globosum or Myrothesium verrucaria when employed in an aqueous medium at a concentration of 1000 parts per million. In another application, the compound 2-chloro- 3,5-dinitro-N-(1,1-dimethylpropargyl) benzamide completely inhibits the growth of Staphlococcus aureus when applied in an aqueous medium at a concentration of 100 parts per million.

Generally, this series of compounds is prepared by reacting the appropriately substituted benzoic acid chloride with an appropriate propargylamine in the presence of an acid acceptor. The amine portion of the propargyl- 3,481,979 Patented Dec. 2, 1969 amine reacts with the carbonyl group of the benzoic acid forming a bond therebetween.

Preferably, the appropriate benzoic acid chloride is added to a solution of the appropriate propargylamine and an acid acceptor, such as triethylamine, potassium carbonate, sodium bicarbonate or pyridine in a suitable inert solvent. The solvent may be any inert, organic so vent, that is, a solvent which does not react with any of the components present or the desired end product. Such solvents include benzene, tetrahydrofuran, ether, 1,2-diethoxyethane, dimethylformamide, and dirnethylacetamide, among others. The mixture is stirred at a temperature of from 0 to about C. for at least one-half hour. Of course, if the reaction is carried out at temperatures above 50 C., the reaction rate is accordingly increased and therefore less time is needed to complete the reaction. Alternatively, the reaction may be carried out in a water solvent system containing an acid acceptor such as an alkali-metal hydroxide, sodium carbonate, or sodium bicarbonate, among others, at a temperature of from about 0 to about 35 for at least one-half hour. Upon cooling, a precipitate forms which is filtered from the solution. The filtrate is concentrated and the product crystallized from an appropriate solvent, such as methanol, ethanol, propanol, cyclohexane, chloroform, a combination thereof, or in combination with water, among others.

The following examples are presented to illustrate this invention but should not be construed as limiting as limiting the various embodiments of this invention. They are presented to illustrate the manufacture of some members of this novel series of compounds.

EXAMPLE I 3-chloro-N- 2-propynyl) -benzamide To a solution of 200 ml. of water and 80 ml. of 10% sodium hydroxide is added 0.1 mole propargylamine fumarate. The resulting solution is chilled and to this is added ml. of 10% sodium hydroxide and a solution of 0.1 mole of 3-chlorobenzoy1 chloride in 200 ml. of acetone, keeping the base in excess at all times. The reaction mixture is stirred for 3 hours until a white precipitate forms. The precipitate is filtered, washed with water and dried at 50 C. The product is crystallized from a methanol-water solution yielding 3-chloro-N-(2- propynyl)-benzamide having a melting point of 130.5"- 131 C. Analysis calculated for C H ClNO: C, 62.00%; H, 4.16%; N, 7.23%. Found: C, 62.19%; H, 4.33%; N 7.09%.

When an equimolar proportion of N-methylpropargylamine fumarate is substituted for the propargylamine fumarate in the above reaction scheme, the 3-chloro-N- 1-lrcr11ethyl-2-propynyl)-benzamide is obtained in similar yie s.

EXAMPLES 2-3 Using a similar procedure as in Example 1, the compounds shown in Table I, having a structure of Formula I (X and Y=H) are made from the correspondingly sub- 2,6-dichloro-N-( 1, l-dimethyl-Z-propynyl) -benzamide To 300 ml. benzene is added 10.4 grams (0.125 mole) of 1,1-dimethyl-Z-propynylamine and 12.6 grams (0.125

mole) of triethylamine. The solution is stirred and chilled while slowly adding a solution of 26.2 grams (0.125 mole) of 2,6-dichlorobenzoyl chloride in 100 ml. of benzene. The temperature is maintained at less than 30 C. during the addition and then allowed to reach room temperature for 2 hours thereafter. A precipitate forms and is filtered from the solution and washed with fresh benzene. The solid is stirred with cool water to dissolve the triethylamine hydrochloride, filtered and dried in a vacuum oven yielding 83% of the product, 2,6-dichloro-N-(1,l-dimethyl-Z-propynyl)-benzamide having a melting point of 145 -147 C.

When an equimolar proportion of l-methyl-Z-propynylamine is substituted for 1,l-dimethyl-Z-propynylamine in the above procedure, 2,6-dichloro-N-(1-methyl-2-propynyl) -benzamide is formed in good yields. When 1- methyl-1-propy1-2-propynylamine is substituted in equimolar proportions for 1,1-dimethyl-Z-propynylamine, 2,6- dichloro-N-( l-methyl-1-propyl-2-propynyl) -benzamide is obtained in good yields.

Following the procedure described in Example 4, several other substituted benzamides may be prepared by merely reacting an equimolar amount of the appropriately substituted benzoyl chloride with an equimolar amount of the desired propargylamine. For example, compounds such as 3,5-diiodo-4-hydroxyphenyl-(1,1-dimethy1-2-propynyl) benzamide; 3,5-dibromo-2-hydroxyphenyl-(1,1- dimethyl-Z-propynyl)-benzamide; 3 hydroxy-2,4,6-triiodophenyl (1,1-dimethyl-2-propynyl)-benzamide; 3,5-diiodo 2 hydroxyphenyl-(l-methyl-Z-propynyl)-benzamide; 5 halo-2 hydroxyphenyl(l-methyl-l-ethyl-Z-propynyl)-benzamide, as well as others may be easily prepared. Table II below gives several examples of compounds prepared according to this method, showing the particular benzoyl chloride starting material, the resulting compound, percent yield and melting point in C. of the product. This table refers to compounds of Formula I wherein X and Y are each CH solution is added a solution consisting of 6 grams (0.1 mole) of n-propylamine in ml. ethanol. The mixture is refluxed for 10 minutes, then cooled to room temperature, and evaporated in a vacuum to yield a yellow solid. The solid is triturated with water to remove the propylamine hydrochloride, and then washed with fresh water and dried in an C. vacuum oven yielding 16.6 grams of 3,5 dinitro 4 n-propylamino-N-(1,1-dimethyl-2-propynyl)-benzamide having a melting point of 12S -126 C.

Where the process utilized involves a benzoyl acid chloride propylamine addition reaction, the X and Y radicals may be varied by substituting the corresponding amine in the reaction scheme. In general, an amine of the formula (CH1) 11H HzN-C-CECH (CH3) H II wherein each n=0 to 4, may be utilized in this type of reaction scheme. As can readily be seen, this series of amines contemplates the amine group being attached to the carbon atom adjacent the triple bond in the hydrocarbon chain.

Others may practice this invention in any of the numerous ways which will be suggested to one skilled in the art upon reading this disclosure. All such practice of the invention is considered to be covered hereby provided it falls within the scope of the appended claims.

We claim:

1. A compound of the formula wherein X and Y are each members selected from the group consisting of hydrogen and loweralkyl having one to four carbon atoms when R is a. member selected from the group consisting of 2-chloro-4-nitrophenyl, 3,5-

Percent M.P

Ex. Starting Material Compound Yield in C.

TAB LE II Percent M.P Ex. Starting Material Compound Yleld in C 5 3,4-dichlorobenzoyl chloride 3,4-dichloro-N-(1,1-dimethylpr0pYny1) ben lde 72 106-1118 6. 2,4-dichlorobenzyl chloride. 2,4-dich1oro-N- (1,1-d1methylpr0pynyl)- bertza lde -107 7. 4-ehlorobenzoy1 chloride 4-eh1oro-N-(1,l-dimethylpropynyl)-benzam1de 72. 8 143-144 8 3-ch1orobenzoyl cholride 3-ehloro-N-(l,1d1methylpr0pynyl) benzamrde- 44. 5 104-106 9 2-chlorobenzoyl chloride 2-chloro-N-(1,1-d1met hylpropynyl) -benzam1de 63. 7 94-95 10- 2-ch1or0-4-n1trobenzoyl chloride. 2-chloro-4-nitro-N-(1,1-drmethylpropynyl)-benzam1de 67 114-115 11 3-nitro-4ch1orobenzoy1 chloride B-nitro-lchlom-N-(1,1-d1methylpropynyl)-benzam1de 81 112-114 12... 3,5-dinitro-4-ehlorobenzoyl chloride 3,5-dinitro-4-eh1oro-N-(1,1-d1methy1propynyl) benzpmide 73 167-169 13 2-nitro-5-chlorobenzoyl chloride z-nitre-aehloro-N-(Ll-dunethylpropynyl)-benzam1de.,... 80 148-150 14... 2-chlor043,5-dinitrobenzoylchloride- 2-chlero-3,5-dinitro-N-(1,l-dimethylpropynyl)-benzamide.. 81 122-125 15 2,4-dich1oro-3 5-dinitrobenzoylchlor1 2,4-dichloro-3,a-dimtro-N-(1,1-dunethy1propynyl)-benrami 70 182-184 16 3,5-dlehlorH-iodo-benzoylehlende. 3,s-diehloro-t-iodo-N-(1,l-dimethylpropynyl)-benzam1d e 66 175-177 17 2-rnethyl-3,5-dinitrobenzoy1chlor1de 2-methyl-3,5-d initro-N-(1,1-d1methylpropynyl) -benzannde-. 73 134-136 18 3,5-dinitro4-dimethylaminobenzoyl chloride..." 3,idinitrq--dnnethylammo-N-(1,1 hmethy1propyny1)- 199-201 GI'IZBIIll e.

19 3,4,5-trich1orobenzoyl chloride 3,4,a-triehloro-N-(l,1-dimethy1-2-propynyl)-benzamide 154-156 EXAMPLE 20 3,5 -dinitro-4-n-propylamino-N-( 1,1-dimethyl-2- propyny1)-benzamide A solution of 15.6 grams (0.05 mole) of 4-chloro-3,5- dinitro-N-(1,l-dimethyl-Z-propynyl)-benzamide dissolved in ml. absolute ethanol is stirred and warmed. To this dinitro-4-chlorophenyl, 2-methyl-3,5-dinitrophenyl, 2- chloro-3,5-dinitropheny1, 3,5-dinitro-4-alkylaminophenyl wherein the alkyl group has one to three carbon atoms, 3,5-dinitro-4-dialkylaminophenyl wherein the alkyl groups have one to three carbon atoms, 2,4-dichloro3,5-dinitrophenyl, 3-nitro-4-chlorophenyl, 2-hydroxy-3,5-dibromophenyl, 3,5-dihalo-4-hydroxyphenyl, 2,4,6-triiodo-3-hydroxphenyl, 2-hydroxy-3,S-diiodophenyl, 2-hydroxy-5- halophenyl and 3,5-dichloro-4-halophenyl; and X and Y are loweralkyl having one to four carbon atoms when R is a member selected from the group consisting of 2-nitro- S-chlorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 2,4-dichlorophenyl and 2,5-dichlorophenyl.

2. The compound according to claim 1 wherein X and Y are each methyl and R is 3-chlorophenyl.

3. The compound according to claim 1 wherein X and Y are each methyl and R is 4-chlorophenyl.

4. The compound according to claim 1 wherein X and Y are each methyl and R is 2,6-dichlorophenyl.

5. The compound according to claim 1 wherein X and Y are each methyl and R is 3,5-diiodo-4-hydroxyphenyl.

r 6. The compound according to claim 1 wherein X a wherein X and Y are each methyl and R is 2,4-dichlorophenyl.

10. The compound according to the formula wherein X and Y are each methyl and R is 2-chlorophenyl.

11. The compound according to claim 1 wherein X and Y are each methyl and R is 2-chloro-4-nitrophenyl.

12. The compound according to claim 1 wherein X and Y are each methyl and R is 3-nitro-4-chlorophenyl.

13. The compound according to claim 1 wherein X and Y are each methyl and R is 3,5-dinitro-4-chlorophenyl.

14. The compound according to claim 1 wherein X and Y are each methyl and R is 2-nitro-5-chlorophenyl.

15. The compound according to claim 1 wherein X and Y are each methyl and R is 2-chloro-3,5-dinitro phenyl.

16. The compound according to claim 1 wherein X and Y are each methyl and R is 2,4-dichloro-3,5-dinitrophenyl.

17. The compound according to claim 1 wherein X and Y are each methyl and R is 3,5-dichloro-4-iodophenyl.

18. The compound according to claim 1 wherein X and Y are each methyl and R is 2-methyl-3,5-dinitrophenyl.

19. A compound according to claim 1 wherein X and Y are each methyl and R is 3,5-dinitro-4-loweralkylaminophenyl wherein the alkyl group has one to three carbon atoms.

20. A compound according to claim 1 wherein X and Y are each methyl and R is 3,5-dinitro-4-diloweralkylaminophenyl wherein the alkyl groups have one to three carbon atoms.

21. The compound according to claim 19 wherein R is 3,5-dinitro-4-n-propylaminophenyl.

22. The compound according to claim 20 wherein R is 3-5-dinitro-4-dimethylaminophenyl.

23. The compound according to the formula References Cited UNITED STATES PATENTS 3,057,919 1962 Pursgloue 260-558 3,226,394 12/1965 Schipper 260-295 OTHER REFERENCES Krughkova et al., J. Org. Chem. of the USSR, vol. 1, p. 230-32 (Feb. 1965) QD 241 I 64.

Marszak ct al., Comptes Rendus, vol. 241, p. 70405 HENRY R. JILES, Primary Examiner H. I. MOATZ, Assistant Examiner US. Cl. X.R.

PMOFJU UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. ,979 Dated December 1Z 1969 Inventor s) Bruce Wayne Horrom and Aldo Jsoeph Cro tti It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

T- Column 1, line 61, add -s-- to the word "inhibit" In Claim 1, in the formula, please delete the formula indicated and substitute Claim 7 delete the word "hyroxy-" and substitute -hydroxy-- SIGNED AND SEALED JUN9 1970 *SEAL) Amen Edmd Fletcher In WILLIAM 1:. saw, a. Atteating Offi r Comissioner of Patents 

